Muscular dystrophies

The most common inherited muscle disease is X-linked recessive Duchenne muscular dystrophy (DMD), which affects 1 in 3300 live male births. Thirty per cent of female carriers may be mildly to moderately affected. In DMD, there is absence of dystrophin, a protein involved in linking the sarcolemma with actin molecules involved in contraction. This is thought to cause breaks in the membrane during muscle contraction. In Becker muscular dystrophy (BMD), dystrophin is present but abnormal.

Boys with DMD develop weakness of the lower limb girdle by the age of 3–6 years. They adopt the Gower manoeuvre to rise from lying (Fig. 1). Weakness then spreads to other muscle groups in the legs and arms. There may be characteristic rubbery enlargement (pseudohypertrophy) of the calf muscles and 30% have a low IQ. Untreated, most are wheelchair-bound by the age of 12 years and die from respiratory complications by the age of 25 years.

Fig. 1 Gower’s manoeuvre.

Investigations include muscle creatine kinase (CK), which is highly elevated, and muscle biopsy, which shows no fibres staining for dystrophin. An ECG is often abnormal. Treatment is supportive, especially prevention of complications, including respiratory infection and contractures. Steroids may slow the progression and respiratory support can prolong survival. Genetic treatments and stem cell implants have yet to provide benefit. BMD follows a milder course with an onset at age 5–45 years; there is also calf pseudohypertrophy and a highly elevated CK, 20–200 times normal. Other dystrophies are described in Table 1; some have been identified as affecting proteins closely linked with dystrophin.

Metabolic myopathies

These rare disorders may affect carbohydrate or lipid metabolism. The enzyme defects can often be identified on muscle biopsy but these may require specialized studies. Three types of symptom occur:

Myotonic syndromes

Myotonic syndromes cause stiffness, limitation of movement and sometimes weakness. Typically, contractions can be provoked by cold and by direct muscle stimulation, for example percussion. There is a characteristic EMG pattern of discharges, which, through a loudspeaker, sounds like a dive-bomber. Hypothyroidism may mimic myotonia.

Dystrophia myotonica is the most common cause (prevalence 2 per 100 000). It is an autosomal dominant disorder of a muscle protein kinase, with variable severity and age of onset and a progressive course, whose genetic basis has been elucidated recently. Patients present with muscle cramps triggered by cold, weakness of the hands or difficulty releasing their grip. There is a characteristic facial appearance with frontal balding, severe temporalis and sternomastoid muscle wasting, bilateral ptosis and facial weakness giving an expressionless, myopathic facies. Limb weakness is worst distally in the hands and feet and there is usually areflexia. The patient cannot suddenly open a clenched fist or release the hand from a handshake. Complications of myotonic dystrophy include cardiac conduction abnormalities and impaired respiratory drive, which may be life-threatening, diabetes mellitus, hypothyroidism, cataracts, male infertility, bowel dysmotility and mental retardation. Myotonia may be improved by phenytoin, procainamide or quinine.

Acquired muscle disease

This usually presents with progressive proximal weakness. It is usually secondary to metabolic disturbance (Box 1), inflammatory disease, infection or toxins. Many are treatable.

Common metabolic abnormalities

These often cause typical proximal weakness but CK, EMG and muscle biopsy are commonly normal. They improve on reversing the metabolic abnormality.

Polymyositis

Polymyositis is the most common inflammatory muscle disease in adults (prevalence 6 per 100 000), especially in women aged 30–60 years. Proximal limb, trunk, neck, pharyngeal and oesophageal muscles may all be involved. The onset is usually subacute or chronic but occasionally acute. Muscles may be painful or tender. CK is usually markedly elevated and EMG often shows myopathic changes with increased spontaneous activity (p. 35). The diagnosis is confirmed by demonstrating inflammatory changes on muscle biopsy. Treatment is with corticosteroids and immunosuppression, most commonly with azathioprine. CK is a marker of disease activity to regulate treatment, which may be long term, and prognosis is good.

Dermatomyositis

This occurs mainly in children, in which similar myositis is combined with a purple ‘heliotrope’ rash around the eyes and a linear red rash over the knuckles and proximal phalanges: ‘Gottron’s papules’ (Fig. 2). Polymyositis and dermatomyositis may occur in isolation or as part of a more widespread collagen–vascular disease. Sarcoidosis or polyarteritis nodosa may produce a similar clinical picture. There is an increased relative risk of neoplasia in both polymyositis (9%) and dermatomyositis (15%) compared with the general population. Lymphoma and ovarian carcinoma are particularly associated.

Fig. 2 Dermatomyositis.

Acute myopathy

This may be autoimmune, due to viral or parasitic infections, drugs, trauma, burns and snake venoms (see Box 1). There may be massive muscle damage with myoglobinaemia and myoglobinuria, causing acute renal tubular necrosis. Rhabdomyolisis may also occur after excessive muscle use: prolonged marches, status epilepticus and neuroleptic malignant syndrome (p. 121).

Malignant hyperthermia

This is a pathological sensitivity in 1 in 50 000 halothane anaesthetics. It is thought to be due to an inherited abnormality of the ryanodine receptor, causing acute myonecrosis and systemic complications. An acute myopathy may also occur in very sick patients in the intensive care setting, especially if treated with steroids and neuromuscular blocking agents.

Inclusion body myositis

This is most common in middle-aged men. It is slowly progressive and tends to affect specific muscles in the early stages, for example brachioradialis. Characteristic inclusion bodies are seen in the cytoplasm and nuclei of myocytes. The nature of the primary process remains unclear. It responds poorly to immunosuppressive treatment.

Other syndromes of muscle stiffness

Stiff man syndrome

This is an autoimmune condition probably reflecting spinal cord disease. There is axial rigidity, which is worse on exertion. It is associated with autoimmune disease, especially diabetes mellitus and antibodies to glutamate decarboxylase. Treatment is with muscle relaxants and immunosuppression.

Neuromyotonia

The pathogenesis is uncertain, although it presents with features suggesting an autoimmune aetiology. There is a gradual onset with twitching or rippling muscles, then stiffness and an abnormal posture, and these symptoms persist in sleep. There is no percussion myotonia. Anti-voltage-gated potassium channel antibodies are found in this condition, resulting in peripheral nerve hyperexcitability.

Muscle disease

Muscle disease usually presents with proximal weakness.

Treatable systemic and inflammatory causes are relatively common.

Occasionally muscle disease may present with myotonia, episodic weakness and exertional symptoms.